Optically active sulphur-containing amino acid derivatives, their preparation, their polymerization to give optically active polymers and the use thereof

ABSTRACT

The invention relates to new optically active sulphur-containing amino acid derivatives, a process for their preparation, their polymerisation to give optically active polymers and the use of these optically active polymers as adsorbents for chromatographic separation of racemates into enantiomers.

This application is a divisional, of application Ser. No. 07/897,196,filed Jun. 11, 1992, now U.S. Pat. No. 5,347,042.

The invention relates to new optically active sulphur-containing aminoacid derivatives, a process for their preparation, their polymerisationto give optically active polymers and the use of these optically activepolymers as adsorbents for chromatographic separation of racemates intoenantiomers.

The separation of enantiomer mixtures into the enantiomers has gainedever more importance-in recent years, because it has been found that theenantiomers of biologically active racemates can differ widely in theiractions and side effects. There is therefore a great interest in theisolation of the individual enantiomers of biologically active racematesor enantiomer mixtures.

The most diverse adsorbents for chromatographic separation of racemateshave already been proposed. The polymeric (meth)acrylic acid derivativesof optically active amino compounds described, for example in Chem. Ber.109 (1976), 1967 or EP-A 379,917 have so far proved to be veryadvantageous adsorbents here, if appropriate in immobilised form oninorganic supports.

It has now been found, surprisingly, that amino acid derivatives whichare derived from sulphur-containing amino acids lead, in combinationwith specific ester and amide radicals, in particular with stericallybulky and rigid ester or amide radicals, to very interesting newoptically active adsorbents. It is to be found, completely unexpectedly,that a sulphur atom in the amino acid component significantly improvesthe separation properties for many separation problems compared with apure hydrocarbon radical. The solubility of the monomers is alsoinfluenced favourably.

A number of active compound racemates, for example, can be separatedconsiderably better on the sulphur-containing separation materialsaccording to the invention than on the adsorbents known from the priorart.

The invention therefore relates to optically active sulphur-containingamino acid derivatives of the formula (I) ##STR1## in which R representshydrogen, methyl or fluorine,

R₁ represents hydrogen or C₁ -C₄ -alkyl, or together with R₂ forms amethylene group or a dimethylene group, which can be mono- ordisubstituted by C₁ -C₄ -alkyl,

R₂ represents a straight-chain, branched or cyclic alkyl radical havingup to 10 C atoms, C₆ -C₁₄ -aryl, ##STR2## C₂ -C₁₀ -acyl or optionallysubstituted benzoyl or benzyl, or together with R₁ forms a bridgedescribed for that radical,

R₃ represents a straight-chain, branched or cyclic alkyl radical havingup to 20 C atoms, which is optionally mono-, di- or trisubstituted byhalogen, alkoxy having 1 to 4 C atoms, aralkoxy having 7 to 16 C atomsor aryl having 6 to 10 C atoms,

and preferably represents a C₁₀ -terpenyl radical, an adamantyl radicalor a decahydronaphthyl radical,

X denotes oxygen or an NR₄ group, in which R₄ represents hydrogen or C₁-C₄ -alkyl, or together with R₃ forms a nitrogen-containing 5- to7-membered ring, which can be mono- or di-C₁ -C₄ -alkyl- or -C₁ -C₆-alkoxycarbonyl-substituted, and

A represents a methylene or dimethylene group which is optionally mono-or di-C₁ -C₄ -alkyl-substituted.

Preferred compounds of the formula (I) are those in which

R represents hydrogen, methyl or fluorine,

R₁ denotes hydrogen or methyl, or together with R₂ forms a methylenegroup, which can be mono- or di-methyl- or mono-tertiarybutyl-substituted, or a dimethylene group,

R₂ represents alkyl having up to 8 C atoms, phenyl or ##STR3## ortogether with R₁ forms a bridge described for that radical, R₃represents a C₁₀ -terpenyl radical, an adamantyl radical or adecahydronaphthyl radical, or represents an alkyl radical or cycloalkylradical having in each case up to 12 C atoms, which is optionally mono-or disubstituted by C₆ -C₁₀ -aryl, C₁ -C₄ -alkoxy, C₃ -C₁₂ -cycloalkylor halogen, it being possible for the aryl and cycloalkyl radicalsmentioned to be substituted again in turn by C₁ -C₄ -alkyl,

X denotes oxygen or an NR₄ group, in which R₄ represents hydrogen or C₁-C₄ -alkyl, or together with R₃ forms a nitrogen-containing 5- to7-membered ring, which can optionally be mono- or di-C₁ -C₄ -alkyl- or-C₁ -C₆ -alkoxycarbonyl-substituted, and

A represents a methylene, dimethylmethylene or a dimethylene unit.

The optically active amino acid derivatives are preferably derived fromoptically active sulphur-containing amino acids, such as, for example,cysteine, penicillamine, or homocysteine. Compounds which are ofparticular interest for this purpose are those in which the SH functionis alkylated, for example S-methyl-cysteine, S-benzyl-cysteine,S-methyl-penicillamine, methionine, ethionine or butionine, or acylated,for example S-acetyl-cysteine, or alkoxycarbonylmethylated, for exampleS-menthoxycarbonylmethyl-cysteine, or bonded to the amino group via anethylene bridge, for example thioproline, 2,2-dimethyl-thioproline,5,5-dimethylthioproline or 2-tert.-butylthioproline.

The use of optically active radicals, for example of the 1-phenylethyl,1-(1-naphthylethyl), 1-(2-naphthylethyl) , the d- or 1-menthyl, d- or1-neomenthyl, d- or 1-bornyl, d- or 1-fenchyl or the d- or 1-pinanylradical, is particularly advantageous for R₃.

The optically active sulphur-containing amino acid derivatives of theformula (I) according to the invention are obtained by reaction ofoptically active sulphur-containing amino acid derivatives of theformula (II) ##STR4## in which

R₁, R₂, R₃, A and X have the meaning given under formula (I),

or acid addition products thereof, with acryloyl derivatives of theformula (III) ##STR5## in which R has the meaning given under formula(I) and

Y represents fluorine, chlorine or bromine, or represents the radical##STR6## if appropriate in the presence of an acid-binding agent ininert organic solvents.

The optically active sulphur-containing amino acid derivatives of theformula (II) used as starting compounds are known or can be prepared byprocesses which are known per se (see Bull. Chem. Soc. Jpn. 37 (1964),191).

Suitable acid addition compounds of the sulphur-containing amino acidsto be used as starting substances are salts of these amino acids withinorganic or organic acids. Mineral acids, such as hydrochloric acid,hydrobromic acid, sulphuric acid or phosphoric acid, or organic acids,such as acetic acid, trifluoroacetic acid or methane-, ethane-, benzene-or toluenesulphonic acid, are preferred.

Suitable solvents are all the organic solvents which are inert under thereaction conditions. Hydrocarbons, such as toluene or petroleum ether,or halogenohydrocarbons, such as methylene chloride, dichloroethane ortrichloroethylene, or ethers, such as tert.-butyl methyl ether, arepreferred.

Possible acid-binding agents are, above all, the customary inorganic ororganic bases; alkali metal or alkaline earth metal hydroxides, such assodium, potassium, lithium, calcium or barium hydroxide, alkali metal oralkaline earth metal carbonates, such as sodium or potassium carbonateor sodium bicarbonate, alkali metal alcoholates, such as sodiummethylate or ethylate or potassium methylate, ethylate ortert.-butylate, or amines, such as triethylamine or pyridine, arepreferably used.

The reaction of the acryloyl derivatives of the formula (III) with thesulphur-containing amino acid derivatives of the formula (II) ispreferably carried out at temperatures from -78° to +100° C., inparticular from -20° to +60° C.

The invention also relates to the optically active polymers andcopolymers which are obtainable by polymerisation or copolymerisation ofthe optically active sulphur-containing acryloylamino acid derivativesof the formula (I) and which contain at least 40 mol %, preferably atleast 50 mol %, of structural units of the formula (IV) ##STR7## inwhich

R, R₁, R₂, R₃, A and X have the meaning given under formula (I).

The optically active polymers of the formula (IV) according to theinvention are preferably in the form of crosslinked insoluble butswellable bead polymers or in a form bonded to finely divided inorganiccarrier materials, such as, for example, silica gel. They can also beprepared as linear polymers which are soluble in suitable organicsolvents. It is furthermore possible for different sulphur-containingacryloylamino acid derivatives of the formula (I) according to theinvention to be copolymerized and for 0.1 to 60, preferably 0.1 to 20mol % of other copolymerisable monomers to be incorporated into thepolymers.

The crosslinked polymers are preferably in the form of small particles(beads) having a particle diameter of 5 to 200 μm. They are prepared,for example, by suspension polymerisation of the optically activesulphur-containing acryloylamino acid derivatives of the formula (I)with 0.5 to 50 mol %, preferably 1 to 30 mol %, particularly preferably3 to 20 mol % (based on the total amount [mol] of the monomers employed) of a suitable crosslinking agent in a manner which is known per se.

The degree of swelling of the (bead) polymers can be adjusted bycustomary methods by the nature and amount of the crosslinking agents.

(Bead) polymers having a degree of swelling (Q) of 1.1 to 12.0,preferably 2.0 to 8.0, have proved suitable for use in practice.

The degree of swelling Q is determined as follows: ##EQU1##

Possible crosslinking agents are compounds which contain at least twopolymerisable vinyl groups. Preferred cross-linking agents arealkanediol diacrylates, such as 1,6-hexanediol diacrylate,1,4-butanediol diacrylate, 1,3-propanediol diacrylate or 1,2-ethyleneglycol diacrylate, or alkanediol dimethacrylates such as 1,4-, 1,3- or2,3-butanediol dimethacrylate, 1,3-propanediol dimethacrylate or1,2-ethylene glycol dimethacrylate, aromatic divinyl compounds, such as,for example, divinylbenzene, divinylchlorobenzene or divinyltoluene,dicarboxylic acid divinyl esters, such as divinyl adipate, divinylbenzenedicarboxylate or divinyl terephthalate, orN,N'-alkylenediacrylamides, such as N,N'-methylenediacrylamide,N,N'-ethylenediacrylamide, N,N'-methylenedimethacrylamide,N,N'-ethylenedimethacrylamide or N,N-dimethyl-ethylenediacrylamide.

Possible agents which form free radicals are the customary agents whichform free radicals. Peroxides, such as, for example, dibenzoyl peroxide,dilauroyl peroxide or di-orthotolyl peroxide, peresters, such astert.-butyl perpivalate or tert.-butyl peroctanoate, or azo compounds,such as, for example, azobisisobutyronitrile (AIBN) are preferred.Mixtures of different agents which form free radicals can also be used.

The polymerisation components are dissolved in a water-immiscibleorganic solvent, preferably an aliphatic or aromatic hydrocarbon, suchas hexane, heptane, isodecane, benzene or toluene, ahalogenohydrocarbon, such as methylene chloride, chloroform, carbontetrachloride or 1,2-dichloroethane, an ester, such as ethyl acetate,butyl acetate or dialkyl carbonates, or a water-insoluble ketone, suchas methyl isobutyl ketone or cyclohexanone.

The organic phase is uniformly distributed in the aqueous solution of aprotective colloid, preferably in an aqueous solution of polyvinylalcohol, polyvinyl-pyrrolidone or a copolymer of methacrylic acid andmethyl methacrylate, with the aid of an effective stirrer. About 1 to20, preferably 2 to 10 parts by weight of aqueous phase are used perpart by weight of organic phase. The polymerisation mixture is heated attemperatures of 30° C. to 100° C., preferably at 40° C. to 80° C., in aninert gas atmosphere, preferably under nitrogen, while stirring. Thepolymerisation time is between 2 and 24, preferably 4 and 12 hours. Thecopolymer obtained in this manner is separated from the liquid phase byfiltration, purified by thorough washing with water and with organicsolvents, such as methanol, ethanol, benzene, toluene, methylenechloride, chloroform or acetone and then dried.

For analytical uses in particular, the optically active polymersaccording to the invention are preferably employed in a form bonded tofinely divided inorganic carriers. Such optically active chromatographyphases can be prepared, for example, by the processes described in DE-A3,706,890.

Polymerisation of the optically active sulphur-containing amino acidderivatives of the formula (I) in the presence of silica gel vinylphases, which are obtainable by the method of B. B. Wheals, J.Chromatogr. 107 (1975), 402 and H. Engelhardt et al., Chromatographia 27(1989), 535, or of silica gel diol phases which have been esterifiedwith (meth)acrylic acid is preferred. This polymerisation can be carriedout in the absence of solvents or in the presence of solvents or ofprecipitating agents for the sulphur-containing poly-N-acryloylamidederivatives. The agents which form free radicals and are used for thepreparation of the bead polymers can also be employed as initiators.

The polymer-modified silica gels preferably contain 1 to 40% by weight,in particular 5 to 30% by weight, of optically active monomer (I), basedon the total weight. They are washed intensively with solvents for thepolymer and dried in vacuo.

Mixtures of two or more of the sulphur-containing N-acryloyl-amino acidderivatives according to the invention, if appropriate also with othercopolymerisable monomers, can of course also be employed here.

The invention furthermore relates to the use of the sulphur-containingpolyacrylamides according to the invention, as such or in crosslinkedform or in a form bonded to silica gel, for chromatographic separationof racemic mixtures into the optical antipodes. The polymers accordingto the invention have proved to be particularly suitable forchromatographic separation of hexahydrocarbazole derivatives, such as,for example,3-r-(4-fluorophenylsulphonamido)-9-(2-carboxyethyl)1,2,3,4,4a,9a-hexahydrocarbazole,and of N-3,5-dinitrobenzoyl-derivatised amino acids, benzodiazepines,such as oxazepam, arylpropionic acids and their amides, such asketoprofen and ibuprofenamide, dihydropyridines, such as, for example,5-methyl1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine-3,5-dicarboxylate,and trifluoroanthrylethanol.

The composition of the mobile phase can be chosen and optimised in thecustomary manner according to the nature and properties of the racemateto be separated. The sulphur-containing polyacrylamides according to theinvention bonded in the silica gel can be employed for chromatographicracemate separations under HPLC conditions.

The ability of the polymers to separate racemates is expressed by thecapacity ratios (k'₁(2) values) for the two enantiomers (1) and (2) andthe resulting enantio-selectivity value α. These chromatographicparameters are defined as follows: ##EQU2##

t₀ =dead time of the column

t₁(2) =Retention time of the enantiomer 1 eluted first or the enantiomer2 eluted later.

The preparative separation of racemic mixtures into their opticalantipodes using the polymers according to the invention is preferablycarried out by column chromatography. For this purpose, it isparticularly advantageous to carry out the chromatographic separationusing bead polymers having a certain particle size distribution; goodseparation efficiencies are obtained with bead polymers having aparticle size distribution of 5 to 200 μm, preferably 15 to 100 μm.

The operating method of column chromatography separation is known. Thepolymer is usually suspended in the mobile phase and the suspension isintroduced into a glass column. After the mobile phase has drained out,the racemate to be separated, dissolved in the mobile phase, is appliedto the column. The column is then eluted with the mobile phase and theenantiomers in the eluate are detected photometrically orpolarimetrically by means of suitable flow-through cells.

Organic solvents or solvent mixtures which swell the polymer employed asthe adsorbent and dissolve the racemate to be separated are usually usedas the mobile phase. Examples which may be mentioned are: hydrocarbons,such as benzene, toluene or xylene, ethers, such as diethyl ether,tert.-butyl methyl ether, dioxane or tetrahydrofuran,halogenohydrocarbons, such as methylene chloride or chloroform, acetone,acetonitrile or ethyl acetate, alcohols, such as methanol, ethanol,n-propanol, isopropanol or n-butanol, or mixtures of the solventsmentioned. Mixtures of toluene with tetrahydrofuran, dioxane orisopropanol have proved to be particularly suitable.

EXAMPLES

I. Preparation method for the optically active sulphur-containingN-acryloylamino acid derivatives (I) (monomers)

Example 1

8.5 g (84 mmol) of triethylamine are added to a solution of 23 g (80mmol) of L-methionine d-menthyl ester in 700 ml of methylene chloride at0° C. A solution of 8.5 g (82 mmol) of methacryloyl chloride in 50 ml ofmethylene chloride is then added dropwise at -10° C. The mixture isallowed to come to room temperature and is then washed with water, 1Nhydrochloric acid and saturated sodium bicarbonate solution. The organicphase is dried over magnesium sulphate. After the solvent has beendistilled off, the residue is recrystallised from n-heptane.

24 g (85%) of N-methacryloyl-L-methionine d-menthyl ester are obtainedin the form of colourless crystals of melting point: 47° C. Opticalrotation [α]_(D) : +66.2° (c=1, CHCl₃).

Instead of by crystallisation, the residue can also be purified bychromatography on silica gel using hexane:ethyl acetate =3:1 as theeluent.

Instead of the free amino ester the corresponding hydrochloride can alsobe employed with the same success. The amount of triethylamine must thenbe doubled.

Example 2

8.1 g (80 mmol) of triethylamine are added to a solution of 21.4 g (75mmol) of L-methionine (1S)-bornyl ester in 650 ml of methylene chlorideat 0° C. A solution of 8.7 g (80 mmol) of fluoroacryloyl chloride in 50ml of methylene chloride is then added dropwise at -10° C. The mixtureis allowed to come to room temperature. It is then washed with water, 1Nhydrochloric acid and saturated sodium bicarbonate solution. The organicphase is dried over magnesium sulphate. After the solvent has beendistilled off, the residue is purified by flash chromatography on silicagel using petroleum ether:ethyl acetate =3:1 as the eluent.

17, g (63%) of N-fluoroacryloyl-L-methionine (1S)-bornyl ester areobtained as a colourless oil having an optical rotation [α]_(D) =+2.0°C. (c=1, CHCl₃).

Example 3

3.5 g (35 mmol) of triethylamine are added to a solution of 8.1 g (30mmol) of (R)-thioproline 1-menthylamide in 100 ml of methylene chlorideat 0° C. A solution of 3.1 g (34 mmol) of acryloyl chloride in 20 ml ofmethylene chloride is then added dropwise at -10° C. The mixture isallowed to come to room temperature.

Working up is as described under Example 1.6 g (64%) ofN-acryloyl-(R)-thioproline 1-menthylamide are obtained in the form ofcolourless crystals of melting point 149° C. (from n-heptane). Opticalrotation [α]_(D) : -184.5° (c=1, CHCl₃).

N-(meth)acryloylamino acid derivatives are obtained from the opticallyactive sulphur-containing amino acid derivatives shown in Table 1 in themanner described. The table also contains the yields, melting points andoptical rotations of the products.

                                      TABLE I                                     __________________________________________________________________________    Monomer synthesis                                                              ##STR8##                                                    (I)                                    Starting             M.p.                                                                              [α].sub.D                                                                       Yield                  Example                                                                             Radical groups  compound   Product   (°C.)                                                                      (c = 1, CHCl.sub.3)                                                                   (% of                  __________________________________________________________________________                                                           theory)                 1    R = CH.sub.3, R.sub.1 = H                                                                     compare text                                                  R.sub.2 = CH.sub.3, R.sub.3 = d-menthyl                                       X = O, A = CH.sub.2CH.sub.2                                              2    R = F, R.sub.1 = H                                                                            "                                                             R.sub.2 = CH.sub.3, R.sub.3 = (1S)-bornyl                                     X = O, A = CH.sub.2CH.sub.2                                              3    R = H, R.sub.1 -R.sub.2 = CH.sub. 2                                                           "                                                             R.sub.3 = l-menthyl,                                                          X = NH, A = CH.sub.2                                                     4    R = H, R.sub.1 = H                                                                            L-methionine                                                                             N-acryloyl-L-                                                                            87 -19.5°                                                                         90                           R.sub.2 = CH.sub.3, R.sub.3 = l-menthyl                                                       l-menthyl ester                                                                          methionine                                         X = O, A = CH.sub.2CH.sub.2                                                                              l-menthyl ester                               5    R = H, R.sub.1 -R.sub.2 = CH.sub.2                                                            (R)-thioproline                                                                          N-acryloyl-(R)-                                                                         oil -29.5°                                                                         72                           R.sub.3 = d-menthyl                                                                           d-menthyl ester                                                                          thioproline d-                                     X = O, A = CH.sub.2        menthyl ester                                 6    R = H, R.sub.1 -R.sub.2 = CH.sub.2                                                            (R)-thioproline                                                                          N-acryloyl-(R)-                                                                         oil -115.3°                                                                        90                           R.sub.3 = l-menthyl                                                                           l-menthyl ester                                                                          thioproline                                        X = O. A = CH.sub.2        l-menthyl ester                               7    R = CH.sub.3, R.sub.1 = H                                                                     L-methionine-                                                                            N-methacryloyl-                                                                          58 +45.0°                                                                         91                           R.sub.2 = CH.sub.3, R.sub.3 = .sup.t Bu                                                       tert.-butyl ester                                                                        L-methionine-                                      X = O, A = CH.sub.2 CH.sub.2                                                                             tert.-butyl ester                             8    R = CH.sub.3, R.sub.1 = H                                                                     L-methionine                                                                             N-methacryloyl-                                                                          80 -27.3°                                                                         81                           R.sub.2 = CH.sub.3, R.sub.3 = l-menthyl,                                                      l-menthyl ester                                                                          L-methionine                                       X = O, A = CH.sub.2 CH.sub.2                                                                             l-menthyl ester                               9    R = CH.sub.3, R.sub.1 = H                                                                     L-methionine                                                                             N-methacryloyl-                                                                         161 -68.3°                                                                         65                           R.sub.2 = CH.sub.3, R.sub.3 = l-menthyl,                                                      l-menthylamide                                                                           L-methionine                                       X = NH, A = CH.sub.2 CH.sub.2                                                                            l-menthylamide                               10    R = H, R.sub.1 = H, R.sub.2 = CH.sub.3,                                                       L-methionine                                                                             N-acryloyl-                                                                             167 -76.1°                                                                         63                           R.sub.3 = l-menthyl                                                                           l-menthylamide                                                                           L-methionine                                       X =  NH, A = CH.sub.2CH.sub.2                                                                            l-menthylamide                               11    R = CH.sub.3, R.sub.1 = H                                                                     L-methionine                                                                             N-methacryloyl-                                                                         192 +38.4°                                                                         85                           R.sub.2 = CH.sub.3, R.sub.3 = d-menthyl                                                       d-menthylamide                                                                           L-methionine                                       X = NH, A = CH.sub.2CH.sub.2                                                                             d-menthylamide                               12    R = H, R.sub.1 = H                                                                            L-methionine                                                                             N-acryloyl-                                                                             209 +19.1°                                                                         55                           R.sub.2 = CH.sub.3, R.sub.3 = d-menthyl,                                                      d-menthylamide                                                                           L-methionine                                       X = NH, A = CH.sub.2 CH.sub.2                                                                            d-menthylamide                               13    R = CH.sub.3, R.sub.1 -R.sub.2 = CH.sub.2                                                     (R)-thioproline                                                                          N-methacryloyl-                                                                         154 -195.3°                                                                        65                           R.sub.3 = l-menthyl, X = NH                                                                   l-menthylamide                                                                           (R)-thioproline                                    A = CH.sub.2               l-menthylamide                               14    R = H, R.sub.1 = H                                                                            L-methionine                                                                             N-acryloyl-                                                                              74 +83.6°                                                                         67                           R.sub.2 = CH.sub.3, R.sub.3 =  d-menthyl                                                      d-menthyl ester                                                                          L-methionine                                       X = O, A = CH.sub.2CH.sub.2                                                                              d-menthyl ester                              15    R = H, R.sub.1 -R.sub.2 = CH.sub.2                                                            (R)-thioproline                                                                          N-acryloyl-                                                                             110 -78.8°                                                                         59                           R.sub.3 = d-menthyl,                                                                          d-menthylamide                                                                           (R)-thioproline                                    X = NH, A = CH.sub.2       d-menthylamide                               16    R = CH.sub.3, R.sub.1 = H                                                                     D-ethionine                                                                              N-methacryloyl-                                                                         127 -73.7°                                                                         66                           R.sub.2 = CH.sub.2 CH.sub.3, R.sub.3 = d-menthyl,                                             d-menthylamide                                                                           D-ethionine                                        X = NH, A = CH.sub.2 CH.sub.2                                                                            d-menthylamide                               17    R = CH.sub.3, R.sub.1 = H                                                                     D-ethionine                                                                              N-methacryloyl-                                                                         178 -28.3°                                                                         44                           R.sub.2 = CH.sub.2 CH.sub.3, R.sub.3 = l-menthyl,                                             l-menthylamide                                                                           D-ethionine                                        X = NH, A = CH.sub.2 CH.sub.2                                                                            l-menthylamide                               18    R = CH.sub.3, R.sub.1 = H                                                                     L-methionine                                                                             N-methacryloyl-                                                                         137 -52.6°                                                                         77                           R.sub.2 = CH.sub.3, R.sub.3 = (S)-                                                            (S)-phenylethyl-                                                                         L-methionine                                       phenylethyl     amide      (S)-phenylethyl                                    X = NH, A = CH.sub.2 CH.sub.2                                                                            amide                                        19    R = CH.sub.3, R.sub.1 = H, R.sub.2 = CH.sub.3,                                                L-methionine                                                                             N-methacryloyl-                                                                         170  +9.1°                                                                         83                           R.sub.3 = d-neomenthyl                                                                        d-neomenthylamide                                                                        L-methionine                                       X = NH, A = CH.sub.2 CH.sub.2                                                                            d-neomenthylamide                            20    R = CH.sub.3, R.sub.1 = H, R.sub.2 = CH.sub.3,                                                L-methionine                                                                             N-methacryloyl-                                                                         121  +7.8°                                                                         56                           R.sub.3 = (R)-phenylethyl                                                                     (R)-phenylethyl-                                                                         L-methionine                                       X = NH,         amide      (R)-phenylethyl                                    A = CH.sub.2 CH.sub.2      amide                                        21    R = CH.sub.3, R.sub.1 = H, R.sub.2 = CH.sub.3,                                                L-methionine                                                                             N-methacryloyl-                                                                         117 -29.8°                                                                         88                           R.sub.3 = phenyl,                                                                             anilide    L-methionine                                       X = NH                     anilide                                            A = CH.sub.2 CH.sub.2                                                   22    R = CH.sub.3, R.sub.1 = H, R.sub.2 = CH.sub.3.                                                L-methionine                                                                             N-methacryloyl-                                                                         114 -18.1°                                                                         80                           R.sub.3 = 3,5-dimethylphenyl,                                                                 3,5-dimethyl-                                                                            L-methionine                                       X = NH          anilide    3,5-dimethyl-                                      A = CH.sub.2 CH.sub.2      anilide                                      23    R = CH.sub.3, R.sub.1 = H, R.sub.2 = CH.sub.3,                                                L-methionine                                                                             N-methacryloyl-                                                                         128 -21.8°                                                                         66                           R.sub.3 = 3-pentyl                                                                            3-pentylamide                                                                            L-methionine                                       X = NH,                    3-pentylamide                                      A = CH.sub.2 CH.sub.2                                                   24    R = CH.sub.3, R.sub.1 = H, R.sub.2 = CH.sub.3,                                                S-methyl-L-                                                                              N-methacryloyl-                                                                         155 -81.4°                                                                         63                           R.sub.3 = l-menthyl                                                                           cysteine   S-methyl-L-cysteine                                                                         (MeOH)                               X = NH,         l-menthylamide                                                                           l-menthylamide                                     A = CH.sub.2                                                            25    R = H, R.sub.1 -R.sub.2 = CH.sub.2                                                            (R)-thioproline                                                                          N-acryloyl-(R)-                                                                         112 -164.7°                                                                        30                           R.sub.3 = (S)-phenylethyl                                                                     (S)-phenylethyl-                                                                         thioproline                                        X = NH,         amide      (S)-phenylethyl-                                   A = CH.sub.2               amide                                        26    R = CH.sub.3, R.sub.1 = H, R.sub.2 = CH.sub.3,                                                L-Methionin-                                                                             N-Methacryloyl-L-                                                                       oil  -3,5°                                                                         58                           R.sub.3 = CH.sub.2 CH.sub.3                                                                   diethylamide                                                                             methionin-                                         X = NCH.sub.2 CH.sub.3,    diethylamide                                       A = CH.sub.2 CH.sub.2                                                   __________________________________________________________________________

II. Polymerisation of the optically active sulphur-containing amino acidderivatives (I)

1. Preparation in a form bonded to silica gel

3.0 g of vinyl-silica gel (prepared from silica gel Si 100/5 μ or 10 μby the method of H. Engelhardt et al., Chromatographia 27 (1989) 535)are dissolved or suspended in 25 ml of toluene with 6.0 g ofsulphur-containing amino acid derivative I and 100 mg ofazobisisobutyronitrile. The apparatus is evacuated and filled withnitrogen three times, while stirring with a magnet. The mixture is thenpolymerised at 80° C. for 45 minutes. After addition of 100 mg of2,6-di-tert.-butyl-4-methylphenol the mixture is cooled rapidly to roomtemperature. The silica gel is filtered off with suction over a G4 fritand stirred twice in chloroform, once in toluene and once in isopropanolfor 15 minutes each time, being filtered off with suction in between.The silica gel is then dried in vacuo (<0.005 atmosphere) at roomtemperature.

The sulphur-containing amino acid derivatives polymerised, the yields ofoptically active silica gel, the nitrogen content thereof and, fromthis, the content of bonded polymer are summarised in the followingTable II.

Similar results of bonded optically active polymer are obtained ifsilica gel diol esterified with methacrylic anhydride is used instead ofvinyl-silica gel.

                  TABLE II                                                        ______________________________________                                        Silica gel phases                                                                    Monomer                    Content of                                         according to                                                                             Yield   N content                                                                             bonded polymer                              Example                                                                              Example No.                                                                              (g)     (%)     (% by weight)                               ______________________________________                                         1A     1         3.5     0.6     15.2                                         2A     2         3.5     0.7     17.8                                         3A     3          3.45   1.5     17.4                                         4A     4         3.2     0.55    13.4                                         6A     6         3.3     0.65    15.1                                         7A     7         3.4     0.8     15.6                                         8A     8         3.4     0.6     15.2                                         9A     9         3.2     0.8     10.1                                        10A    10         3.3     1.35    16.4                                        11A    11         3.4     1.2     15.2                                        12A    12         3.5     1.4     17.0                                        13A    13         3.1     0.2      2.4                                        14A    14         3.2     0.65    15.9                                        15A    15         3.6     2.0     23.2                                        16A    16         3.3     0.5      6.6                                        17A    17         3.4     1.2     15.8                                        18A    18         3.5     1.8     20.6                                        19A    19         3.3     1.15    14.5                                        20A    20         3.4     1.5     17.2                                        21A    21         3.4     1.45    15.2                                        22A    22         3.5     1.5     17.1                                        23A    23         3.4     1.75    17.9                                        24A    24         3.1     1.3     15.8                                        ______________________________________                                    

2. Preparation in the form of bead polymers

A solution of 13.5 g of sulphur-containing amino acid derivative I, 1.5g of ethylene glycol dimethacrylate and 0.3 g of azobisisobutyronitrilein 45 g of chloroform is dispersed in a solution of 5 g of polyvinylalcohol in 130 ml of water, while stirring at 450 revolutions/min. Theapparatus is evacuated and filled with nitrogen several times.Polymerisation is then carried out at 55° C. for 16 hours undernitrogen. The polymerisation mixture is then stirred into 2 to 3 l ofwater and, after the bead polymer has settled, the liquid phase isdecanted. The bead polymer is freed from fine particles (polymer havinga particle size of less than 10 μm) by suspending in water and decantingoff the liquid phase 3 to 4 times and, after intensive washing withacetone, is dried to constant weight at 60° C.

The sulphur-containing amino acid derivatives used for thepolymerisation, the yields in which the polymers were obtained, theparticle size thereof and the volume of the resulting bead polymers inthe dried (V₂) and swollen (V_(q)) state (swelling agent: toluene =T ortoluene/tetrahydrofuran =3:2 v/v mixture =T/T) are summarised in thefollowing Table III.

                  TABLE III                                                       ______________________________________                                        Bead polymers                                                                        Monomer            Particle                                                   according to                                                                             Yield   size    V.sub.s                                                                             V.sub.q                               Example                                                                              Example No.                                                                              (g)     (μm) (ml/g)                                                                              (ml/g)                                ______________________________________                                         8B     8         12.0    15-60   1.9   5.1                                    9B     9         12.1    10-50   1.7   5.9                                   10B    10         11.4    10-30   1.9   6.7                                   11B    11         11.7    15-60   2.0   5.7                                   18B    18         13.6    10-60   1.8   4.4                                   19B    19         11.5    20-90   1.9   4.9                                   20B    20         11.7    15-85   1.8   4.6                                   23B    23         11.0    15-85   1.9   4.4                                   ______________________________________                                    

III. Use of the optically active polymers of sulphur-containing aminoacid derivatives (I) as adsorbents for racemate separation

    ______________________________________                                        The following test racemates                                                  were used for the chromatographic separations:                                ______________________________________                                        Racemate No. 1:                                                                             3-r-(4-fluorophenylsulphonamido)-                                             9-(2-carboxyethyl)-1,2,3,4,4a,9a-hexa-                                        hydrocarbazole                                                  Racemate No. 2:                                                                             Oxazepam                                                        Racemate No. 3:                                                                             Ketoprofen                                                      Racemate No. 4:                                                                             5-Methyl 1,4-dihydro-2,6-dimethyl-                                            4-(2-trifluoromethylphenyl)pyridine-                                          3,5-dicarboxylate                                               Racemate No. 5:                                                                             N-3,5-dinitrobenzoylleucine                                     Racemate No. 6:                                                                             Trifluoroanthrylethanol                                         Racemate No. 7:                                                                             Ibuprofenamide                                                  ______________________________________                                    

The polymers bonded to silica gel were employed in steel columns(internal diameter: 4 mm; length: 25 cm). The columns were eluted withn-heptane/tetrahydrofuran mixtures: 1:1 (vol/vol) =eluting agent a, 1:2=eluting agent b. The flow rate of the mobile phase was 1 ml/min.

The bead polymers were employed in a glass column (internal diameter:1.2 cm; bed height: 25-30 cm). The column was eluted with atoluene/tetrahydrofuran mixture 3:1 (vol/vol). The flow rate of themobile phase was 0.5 ml/minute.

The results obtained in the chromatographic separation of the varioustests racemates (enantioselectivity α and capacity ratio k'₁) and theeluting agents used are summarised in Table IV. An example is given herefor the adsorbents according to the invention in comparison with theanalogous sulphur-free phase (see EP-A 379,917). It is found that thesulphur-free norleucine phase is inferior to the sulphur-containingmethionine phase according to the invention.

                                      TABLE IV                                    __________________________________________________________________________    Separation results                                                                   Stationary phase                                                              from N-methacryloyl-L-methionine                                                                       from N-methacryloyl-L-norleucine                     l-menthylamide (→9A)                                                                            l-menthylamide (EP 379,917)                           ##STR9##                                                                                               ##STR10##                                    Racemate                                                                             Eluent         k'.sub.1                                                                           alpha                                                                              Eluent         k'   alpha                     __________________________________________________________________________    No. 1  Heptane:THF = 1:2                                                                            2.88 5.00 no separation                                 No. 2  Heptane:THF = 1:1                                                                            2.67  4.32                                                                              Heptane:THF = 1:2                                                                            4.00 1.34                      No. 3  Heptane:THF = 3:1                                                                            3.06 1.09 no separation                                 No. 4  Heptane:THF = 1:1                                                                            1.64 2.14 Heptane:THF = 1:1                                                                            2.77 1.68                      No. 5  Heptane:THF = 1:1                                                                            0.56 1.63 Heptane:THF = 1:1                                                                            0.63 1.17                      No. 6  Heptane:isopropanol = 10:1                                                                   1.33 1.26 Heptane:isopropanol = 10:1                                                                   1.13 1.16                      No. 7  Heptane:THF = 1:1                                                                            1.74 1.82 Heptane:THF = 1:1                                                                            1.99 1.77                      __________________________________________________________________________

We claim:
 1. An optically active polymer containing at least 40 mol % ofstructural units of the formula ##STR11## in which R representshydrogen, methyl or fluorine,R₁ represents hydrogen or C₁ -C₄ -alkyl, ortogether with R₂ forms a methylene group or a dimethylene group whichcan be mono- or disubstituted by C₁ -C₄ -alkyl, R₂ represents astraight-chain, branched or cyclic alkyl radical having up to 10 Catoms, C₆ -C₁₄ -aryl, ##STR12## C₂ -C₁₀ -acyl or optionally substitutedbenzoyl or benzyl, or together with R₁ forms a bridge described for thatradical, R₃ represents a straight-chain, branched or cyclic alkylradical having up to 20 C atoms, which is optionally mono-, di- ortrisubstituted by halogen, alkoxy having 1 to 4 C atoms, aralkoxy having7 to 16 C atoms or aryl having 6 to 10 C atoms, or a C₁₀ -terpenylradical, an adamantyl radical or a decahydronaphthyl radical, X denotesan NR₄ group, in which R₄ represents hydrogen or C₁ -C₄ -alkyl, ortogether with R₃ forms a nitrogen-containing 5- to 7-membered ring,which can be mono- or di-C₁ -C₄ -alkyl- or -C₁ -C₆-alkoxycarbonyl-substituted, and A represents a methylene or dimethylenegroup which is optionally mono- or di-C₁ -C₄ -alkyl-substituted.
 2. Apolymer according to claim 1, in whichR represents hydrogen, methyl orfluorine, R₁ denotes hydrogen or methyl, or together with R₂ forms amethylene group which can be mono- or di-methyl- or mono- tertiarybutyl-substituted, or a dimethylene group, R₂ represents alkyl having upto 8 C atoms, phenyl or ##STR13## or together with R₁ forms a bridgedescribed for that radical, R₃ represents a C₁₀ -terpenyl radical, anadamantyl radical or a decahydronaphthyl radical, or represents an alkylradical or cycloalkyl radical having in each case up to 12 C atoms,which is optionally mono- or disubstituted by C₆ -C₁₀ -aryl, C₁ -C₄-alkoxy, C₃ -C₁₂ -cycloalkyl or halogen, it being possible for the aryland cycloalkyl radicals mentioned to be substituted again in turn by C₁-C₄ -alkyl, X denotes an NR₄ group, in which R₄ represents hydrogen orC₁ -C₄ -alkyl, or together with R₃ forms a nitrogen-containing 5- to7-membered ring, which can optionally be mono- or di-C₁ -C₄ -alkyl- or-C₁ -C₆ -alkoxycarbonyl-substituted, and A represents a methylene,dimethylmethylene or a dimethylene group.
 3. A polymer according toclaim 1, which contains the amino acid sequence of the optically activesulphur-containing amino acids cysteine, homocysteine, or penicillamineand the SH function is alkylated, arylated, alkoxycarbonylmethylated orbonded to the amino group by an alkylene bridge.
 4. A polymer accordingto claim 1, containing units of the monomer of the formula ##STR14## 5.A polymer according to claim 1, containing units of the monomer of theformula ##STR15##
 6. A polymer according to claim 1, containing units ofthe monomer of the formula ##STR16##
 7. A polymer according to claim 1,containing units of the monomer of the formula ##STR17##
 8. In theseparation of racemic mixtures into their optical antipodes by contactwith a polymeric adsorbent and selective elution therefrom, theimprovement wherein the polymer of said adsorbent comprises a polymeraccording to claim
 1. 9. A polymer according to claim 1, bonded to afinely divided inorganic carrier.
 10. A polymer according to claim 4,bonded to a finely divided silica gel.
 11. The method according to claim8, wherein the polymer of said adsorbent is bonded to a finely dividedinorganic carrier.
 12. The method according to claim 8, wherein thepolymer of said absorbent contains the amino acid sequence of theoptically active sulphur-containing amino acids cysteine, homocysteine,or penicillamine and the SH function is alkylated, arylated,alkoxycarbonylmethylated or bonded to the amino group by an alkylenebridge and the polymer is bonded to a finely divided silica gel.